The aims of this proposal are to (1) improve comparative modeling so that atomic level accuracy models can be routinely generated starting from structures of homologous proteins, (2) transform the process of NMR structure determination by making possible the determination of atomic level accuracy models without side chain assignments, and (3) enable the determination of high resolution structures from 3-4.5 E resolution density maps. These methodological advances will be extended to enable structure determination of membrane proteins and large homo-oligomers based on datasets not sufficient to allow structure determination using conventional methods.

Public Health Relevance

The proposed work could transform the process of macromolecular structure determination, making it possible to determine accurate structures rapidly with less cost and effort, and to determine atomic level structures for proteins and complexes for which this is not currently possible. Such structures could provide insight into fundamental biological processes and the basis for disease causing mutations, and allow the structure based design of new therapeutics.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Macromolecular Structure and Function D Study Section (MSFD)
Program Officer
Preusch, Peter C
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University of Washington
Schools of Medicine
United States
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Park, Hahnbeom; DiMaio, Frank; Baker, David (2016) CASP11 refinement experiments with ROSETTA. Proteins 84 Suppl 1:314-22
Safarian, Schara; Rajendran, Chitra; Müller, Hannelore et al. (2016) Structure of a bd oxidase indicates similar mechanisms for membrane-integrated oxygen reductases. Science 352:583-6
Wang, Ray Yu-Ruei; Kudryashev, Mikhail; Li, Xueming et al. (2015) De novo protein structure determination from near-atomic-resolution cryo-EM maps. Nat Methods 12:335-8
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Kudryashev, Mikhail; Wang, Ray Yu-Ruei; Brackmann, Maximilian et al. (2015) Structure of the type VI secretion system contractile sheath. Cell 160:952-62
Antala, Sagar; Ovchinnikov, Sergey; Kamisetty, Hetunandan et al. (2015) Computation and Functional Studies Provide a Model for the Structure of the Zinc Transporter hZIP4. J Biol Chem 290:17796-805
Ovchinnikov, Sergey; Kinch, Lisa; Park, Hahnbeom et al. (2015) Large-scale determination of previously unsolved protein structures using evolutionary information. Elife 4:e09248
Blok, Neil B; Tan, Dongyan; Wang, Ray Yu-Ruei et al. (2015) Unique double-ring structure of the peroxisomal Pex1/Pex6 ATPase complex revealed by cryo-electron microscopy. Proc Natl Acad Sci U S A 112:E4017-25
Park, Hahnbeom; DiMaio, Frank; Baker, David (2015) The origin of consistent protein structure refinement from structural averaging. Structure 23:1123-8
Ovchinnikov, Sergey; Kamisetty, Hetunandan; Baker, David (2014) Robust and accurate prediction of residue-residue interactions across protein interfaces using evolutionary information. Elife 3:e02030

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